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  • Review Article
  • Published:

Testosterone replacement therapy and cardiovascular risk

Abstract

Testosterone is the main male sex hormone and is essential for the maintenance of male secondary sexual characteristics and fertility. Androgen deficiency in young men owing to organic disease of the hypothalamus, pituitary gland or testes has been treated with testosterone replacement for decades without reports of increased cardiovascular events. In the past decade, the number of testosterone prescriptions issued for middle-aged or older men with either age-related or obesity-related decline in serum testosterone levels has increased exponentially even though these conditions are not approved indications for testosterone therapy. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. However, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess cardiovascular events; therefore, the cardiovascular safety of this therapy remains unclear. In this Review, we provide an overview of epidemiological data on the association between serum levels of endogenous testosterone and cardiovascular disease, prescription database studies on the risk of cardiovascular disease in men receiving testosterone therapy, randomized trials and meta-analyses evaluating testosterone replacement therapy and its association with cardiovascular events and mechanistic studies on the effects of testosterone on the cardiovascular system. Our aim is to help clinicians to make informed decisions when considering testosterone replacement therapy in their patients.

Key points

  • Population studies suggest that low serum levels of endogenous testosterone are a risk factor for cardiovascular events, although these studies cannot establish causality or exclude reverse causality, and some of these associations might result from residual confounding.

  • Although many retrospective studies show no association, some retrospective studies of prescription databases have shown a higher risk of cardiovascular events in men receiving testosterone, with the risk increasing early after treatment initiation.

  • Meta-analyses of randomized, controlled trials of testosterone replacement therapy report conflicting findings, probably because the included trials lacked power or the duration was too short to assess cardiovascular events.

  • The TRAVERSE trial, the first trial of testosterone therapy that is adequately powered to assess cardiovascular events, began in 2018, and its findings might take a decade to become available.

  • Until the results of the TRAVERSE trial are available, clinicians should individualize testosterone treatment after having an informed discussion with their patients about the risks and benefits of testosterone replacement therapy.

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Fig. 1: Time-to-event analysis of cardiovascular adverse events in the TOM trial.
Fig. 2: Effects of testosterone treatment on coronary artery plaques in clinical trials.
Fig. 3: Meta-analyses of clinical trials of testosterone replacement therapy.
Fig. 4: Cardiovascular targets and effects of testosterone.
Fig. 5: Molecular mechanisms of testosterone modulation of vascular tone.
Fig. 6: Effects of testosterone on cardiac electrophysiology.

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Gagliano-Jucá, T., Basaria, S. Testosterone replacement therapy and cardiovascular risk. Nat Rev Cardiol 16, 555–574 (2019). https://doi.org/10.1038/s41569-019-0211-4

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